| Summary: | Efficient treatment of disseminated triple-negative breast cancer (TNBC) remains an unmet clinical need. The epithelial cell adhesion molecule (EpCAM) is often overexpressed on the surface of TNBC cells, which makes EpCAM a potential therapeutic target. Radionuclide molecular imaging of EpCAM expression might permit selection of patients for EpCAM-targeting therapies. In this study, we evaluated a scaffold protein, designed ankyrin repeat protein (DARPin) Ec1, for imaging of EpCAM in TNBC. DARPin Ec1 was labeled with a non-residualizing [<sup>125</sup>I]I-<i>para</i>-iodobenzoate (PIB) label and a residualizing [<sup>99m</sup>Tc]Tc(CO)<sub>3</sub> label. Both imaging probes retained high binding specificity and affinity to EpCAM-expressing MDA-MB-468 TNBC cells after labeling. Internalization studies showed that Ec1 was retained on the surface of MDA-MB-468 cells to a high degree up to 24 h. Biodistribution in Balb/c nu/nu mice bearing MDA-MB-468 xenografts demonstrated specific uptake of both [<sup>125</sup>I]I-PIB-Ec1 and [<sup>99m</sup>Tc]Tc(CO)<sub>3</sub>-Ec1 in TNBC tumors. [<sup>125</sup>I]I-PIB-Ec1 had appreciably lower uptake in normal organs compared with [<sup>99m</sup>Tc]Tc(CO)<sub>3</sub>-Ec1, which resulted in significantly (<i>p</i> < 0.05) higher tumor-to-organ ratios. The biodistribution data were confirmed by micro-Single-Photon Emission Computed Tomography/Computed Tomography (microSPECT/CT) imaging. In conclusion, an indirectly radioiodinated Ec1 is the preferable probe for imaging of EpCAM in TNBC.
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